Atrial fibrillation (AF) is the most common form of cardiac dysrhythmia. The occurrence of AF increases with age: the prevalence rises from 0.5% of people in their 50s, to 5% of people over the age of 65 years, and to nearly 10% of the population over 80 (Benjamin et al., 1998; Wang et al., 2003). AF is a major cause of morbidity and mortality as it increases the risk of death, congestive heart failure, and embolic phenomena including stroke (Benjamin et al., 1998; Wang et al., 2003). AF is believed to be a lifetime risk in an aging population, and therefore is emerging as a major public-health concern (Lloyd-Jones et al., 2004; Lip and Tse, 2007).
Antiarrhythmic drug therapy remains the principal approach for suppressing AF and its recurrence. Class III anti-arrhythmic agents are effective in treating AF (Nademanee, 1992; Roden, 1993), but have major limitations, such as inducing severe ventricular arrhythmia (i.e. long QT syndrome) (Roden and Anderson, 2006). Therefore, a key objective among the current strategies for suppressing AF is the development of antiarrhythmiic agents that preferentially affect atrial rather than ventricular electrical parameters (Burashnikov et al., 2007; Blaauw et al., 2004).
Class III antiarrhythmic agents are drugs that selectively prolong cardiac action potential duration without significant cardiac suppression. Currently available drugs such as sotalol and amiodarone have Class III properties (Sharma et al., 1999; Nattel and Singh, 1999), but they also have other effects. Sotalol also possesses Class II effects (β-adrenoceptor block) causing cardiac depression and is contraindicated in certain susceptible patients (D'Aloia et al., 2005; DeWitt and Waksman, 2004). Amiodarone possesses multiple electrophysiological actions and is limited by side effects (Nademanee, 1992).
Other class III antiarrhythmic agents include dofetilide (UK-68,798), almokalant (H234/09), and E-4031. These compounds, including sotalol, show a predominant block of IKr. However, amiodarone is a blocker of IKs (Balser et al., 1991), and it also blocks INa, and ICa.
Because IKr is present in both the atrium and ventricle of the human heart (Wang et al., 1994; Li et al., 1996b), IKr blockers increase action potential duration and refractoriness in both atria and ventricle. Theoretically they represent potentially useful agents for the treatment of arrhythmias like AF; however, these agents have a liability in that they have an enhanced risk of proarrhythmia at low heart rates. For example, torsades de points has been observed when these compounds are utilized (Roden and Anderson, 2006). This exaggerated effect at low heart rates has been termed “reverse frequency-dependence”, and differs from frequency-independent or frequency-dependent actions (Hondeghem, 1992).
In intact human atrial myocytes, an ultra-rapidly activating delayed rectifier K+ current IKur, which is also known as the sustained outward K+ current (IKsus or Iso) has been identified (Wang et al., 1993). This current has properties and kinetics similar to those of the cloned human cardiac K+ channel hKv1.5 stably expressed in HEK 293 cells (Fedida et al., 1993). The ultra-rapidly activating delayed rectifier IKur is found to be functionally present in the atrium, but not in the ventricle of human heart (Li et al, 1996b). Because IKur is rapidly activated, and has a limited slow inactivation, IKur is believed to contribute significantly to the repolarization in human atrium. Blockage of IKur will slow repolarization and prolong refractoriness selectively in the human atrium without causing the delay in ventricular repolarization. A selective IKur blocker would not produce arrhythmogenic after depolarizations and acquired long QT syndrome observed during treatment with current Class III drugs. Therefore, human atrial IKur and/or human Kv1.5 are believed to be potential targets for developing selective anti-atrial fibrillation agents (Brendel and Peukert, 2003; Peukert et al., 2003). However, there is no such drug commercially available yet.